Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity

Abstract

Although loss of epithelial integrity is a hallmark of advanced cancer, it remains poorly understood whether genetic alterations corrupting this integrity causally facilitate tumorigenesis. We show that conditional deletion of tumor suppressor gene Lkb1 (Par-4) in the mammary gland compromises epithelial integrity manifested by mislocalization of cell polarity markers, lateralization of tight junctions, deterioration of desmosomes and basement membrane (BM), and hyperbranching of the mammary ductal tree. We identify the desmosomal BM remodelling serine protease Hepsin as a key factor mediating Lkb1 loss-induced structural alterations in mammary epithelium and BM fragmentation. Although loss of Lkb1 alone does not promote mammary tumorigenesis, combination of Lkb1 deficiency with oncogenic c-Myc leads to dramatic acceleration in tumor formation. The results coupling Lkb1 loss-mediated epithelial integrity defects to mislocalization of serine protease Hepsin and to oncogenic synergy with c-Myc imply that Lkb1 loss facilitates oncogenic proliferation by releasing epithelial cells from structural BM boundaries.breast cancer | mouse model

Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

“…We reported that loss of LKB1 does not induce palpable tumours during the lifetime of the mice but leads to mild abnormalities in the mammary gland, such as hyperbranching, partial disorganization of apical polarity and incomplete basement membrane. However, combining LKB1 deficiency with oncogenic MYC dramatically accelerates the appearance of mammary tumours in comparison with glands exposed to oncogenic MYC alone [32]. The study shows that both MYC þ and MYC þ ;LKB1 2 tumours are histopathologically mostly adenocarcinomas and not informative as such regarding the possible mechanisms underlying accelerated tumorigenesis.…”

“…Investigating MMECs, isolated from aforementioned mice, in ex vivo three-dimensional cultures, we observed that MYC þ epithelial structures were hyperplastic but still maintained the rounded morphology. By contrast, the MYC þ ;LKB1 2 structures showed extensive branching and lacked basement membrane components, such as nidogen and collagen IV [32]. A panel of small molecule inhibitors tested in a rescue assay did not support specific roles for MMPs, but instead suggested involvement of TTSPs in deterioration of basement membrane.…”

“…A selective deletion of LKB1 in the adult mammary gland, obtained by crossing mice with floxed LKB1 alleles with mice harbouring a lactogenic hormone-inducible WAP-Cre construct leads to many similar phenotypes observed in the in vitro three-dimensional cultures. The LKB1-deficient mammary ductal and alveolar structures express a disorganized pattern of apical markers and incomplete basement membrane as well as displaying enhanced branching of the ducts [32]. However, inactivation of LKB1 may lead to strikingly different phenotypes in different epithelial tissues as discussed next.…”

“…In the mammary gland, loss of LKB1 simultaneously leads to defects in cell polarity, cell junctions and basement membranes [32]. In the study of Lo et al [71], polarity defects were not observed in embryonic lung tissue after inactivation of LKB1.…”

The rise and fall of central dogmas

“…This can be exemplified by the study of Partanen et al 19 The forward propelling force of the potential tumor cell-or its quiescence-is primarily determined by compounded changes at the cellular level. Oncogene activation initiates the drive.…”